Cholesterol in ASD: Characterization and Treatment

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
ClinicalTrials.gov Identifier:
NCT00965068
First received: August 24, 2009
Last updated: March 14, 2014
Last verified: February 2014
  Purpose

Background:

- Autism spectrum disorders (ASD) are developmental disabilities characterized by impaired social interaction and repetitive and/or stereotypical behaviors. Research studies suggest that some individuals with ASD have very low blood cholesterol levels. This low cholesterol level and other abnormal sterol levels may be important markers for

subtypes of ASD. Providing additional cholesterol to the diets of children with ASD may help improve behavior.

- These findings will guide the medical community in identifying individuals who should be tested for sterol disorders. This study will also help researchers learn whether adding extra cholesterol to the diet will improve behavioral and other autism spectrum characteristics seen in individuals with ASD and low cholesterol.

Objectives:

  • To determine cholesterol levels in children with autism spectrum disorders.
  • To compare behavioral and other characteristics among children who have autism spectrum disorders and high, low, or normal cholesterol levels.
  • To determine whether adding cholesterol to the diet will improve behavioral and other characteristics in individuals with ASD and low cholesterol.

Eligibility:

- Children between the ages of 4 and 12 who have been diagnosed with an autism spectrum disorder.

Design:

  • Initial screening study will involve a collection of blood samples (for study purposes and cholesterol testing).
  • Children who have low cholesterol levels will take part in a study in which they will receive either cholesterol supplementation or a placebo, and will have detailed physical and psychological examinations to measure possible improvement in behavioral or other characteristics.
  • Children who have high or normal cholesterol levels will have further blood samples taken, and will undergo an additional set of examinations for comparison purposes.
  • Researchers may request blood or DNA samples from other family members (parents or siblings), which will be collected through blood draws and cheek swabs.

Condition Intervention Phase
Autism
Asperger Disorder
PDD-NOS
Other: Cholesterol
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: Cholesterol in Autism Spectrum Disorder (ASD): Characterization and Treatment

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Behavioral Changes

Enrollment: 44
Study Start Date: July 2009
Study Completion Date: November 2013
Intervention Details:
    Other: Cholesterol
    N/A
Detailed Description:

Pilot work suggests that some individuals with autism spectrum disorders (ASD) have very low blood cholesterol levels. This low cholesterol level and other abnormal sterol levels may be important markers for subtypes of ASD. The proposed trial aims to characterize any clinical differences between low-cholesterol ASD and normal-or-high-cholesterol ASD and to test the response of individuals with ASD and low cholesterol to increased cholesterol in the diet.

Evidence for the role of low cholesterol in causing ASD in a subgroup of individuals comes from five sources. First, half of individuals with Smith-Lemli-Opitz syndrome (SLOS) meet the behavioral criteria for autistic disorder (Tierney et al, 2001), and three quarters have some type of ASD (Sikora et al, 2006). Second, in individuals with SLOS, the lower the cholesterol was in the blood and cerebrospinal fluid, the more severe were the autism and IQ and adaptive function deficits. Third, in SLOS, improvement was found in social and communication abilities with added dietary cholesterol. Fourth, cholesterol was low in a pilot study of 100 children with autism of unknown cause (Tierney et al, 2006). Fifth, it is becoming increasingly clear that cholesterol plays a pivotal role in several aspects of brain development.

This proposal is designed to 1) determine the prevalence of hypocholesterolemia in ASD individuals (ASD+Hypo); 2) determine the prevalence of hypercholesterolemia (in ASD individuals (ASD+Hyper); 3) determine the rate of SLOS in the ASD subjects; 4) determine the phenotype (physical, behavioral, and developmental) at less than the 5th centile (ASD+Hypo) and greater than the 95th centile (ASD+Hyper) individuals and normal cholesterol (ASD+Normal) in the ASD subjects; 5) test the efficacy of dietary cholesterol supplementation in ASD individuals with hypocholesterolemia; 6) determine whether a raised dose of cholesterol supplementation is more effective than a lower dose; and 7) create a repository of biomaterial samples from individuals with ASD and their biological family members.

Three sites (Kennedy Krieger Institute [KKI], Ohio State University [OSU], and the National Institutes of Health [NIH]) will collaborate to accomplish the objectives of this study. In addition to defining the frequency of altered cholesterol homeostasis in ASD, 60 youths (20 at each site) with ASD plus hypocholesterolemia will enter a 12-week, double-blind, placebo-controlled trial immediately followed by a 12-week open-label cholesterol trial to test the efficacy of dietary cholesterol supplementation. Outcome measures will include standard tests of behavior, communication, and other autism features.

These findings will guide the medical community in identifying individuals who should be tested for sterol disorders. This study will also help researchers learn whether adding extra cholesterol to the diet will improve behavioral and other autism spectrum characteristics seen in individuals with ASD and low cholesterol. The results of this study may help individuals with hypocholesterolemic ASD by the knowledge of the therapeutic value and safety of the use of cholesterol supplementation both biochemically and behaviorally. If improvement is demonstrated, it opens a new window to understanding the neurologic mechanisms of ASD. This knowledge may also be helpful for hypocholesterolemic individuals with ASD in that this newly identified population will benefit from such supplementation. Even if cholesterol supplementation is found to not be effective, important behavioral phenotype and developmental information will be obtained that might be useful in identifying subjects with ASD plus cholesterol abnormalities.

  Eligibility

Ages Eligible for Study:   4 Years to 12 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION/EXCLUSION CRITERIA:

Screening Visit:

Inclusion:

  • Parents agree to use a multivitamin with minerals if their child is selected to continue to the cholesterol supplementation clinical trial.
  • Parents agree to not change the doses of other dietary supplement throughout the clinical trial, including megavitamins.
  • Supplements or medications that are not meant to lower cholesterol levels but are likely to have cholesterol-lowering effects (such as Omega 3 or fish oil) will be permitted if the dose has been stable for at least 3 months prior to the initial screening visit.
  • Male or female between the ages of 4.0-12.0 years at the time of consent/assent.
  • Clinically diagnosed with an ASD for which no cause has been detected.
  • Anticonvulsants used for the treatment of a seizure disorder will be permitted if the dosage has been stable for 3 months, and the subject is seizure free for at least 3 months.

Exclusion:

  • Known pregnancy.
  • Subject has SLOS or known cholesterol synthesis/regulation disorder.
  • The subject has had an anticonvulsant dose change in the preceding 3 months or a seizure in the preceding 3 months.
  • DSM-IV diagnosis of Rett Disorder, childhood disintegrative disorder, schizophrenia, another psychotic disorder, or substance abuse.
  • A significant medical condition such as heart disease, hypertension, liver or renal failure, pulmonary disease, diabetes, or unstable seizure disorder identified by history, physical examination, or laboratory tests.
  • Dietary supplementation doses, including megavitamins, have changed within the preceding 3 months.
  • Currently on or has taken a statin or other medication meant to lower cholesterol within the preceding 3 months.
  • Currently on or has taken dietary cholesterol supplementation within the preceding 3 months.
  • Subjects will be excluded if they are on other medications or supplements that affect cholesterol or other lipid levels.
  • Subjects with gastronomy feeding tubes (G-tubes) will be excluded.
  • Subjects for whom English is not the primary language will be excluded.

(No subjects will be excluded based on race, ethnicity or gender).

Characterization Visit:

Inclusion:

  • Same inclusion criteria as the Screening Visit.
  • Participants must have a mental age of 18 months as measured at the Characterization Visit by the age-appropriate form of the Stanford Binet-V, the Differential Abilities Scale, or the Mullen Scales of Early Learning (N.B. potential subjects who test below 18 months of age, but are otherwise eligible, may be admitted to the study following a case review convened by the Multisite Steering Committee).
  • Child must have an ASD diagnosis using DSM-IV and clinical judgment in order to proceed to the other components of the Characterization Visit.
  • Neuroleptics will be permitted for the ASD+Hypo group only if the dosage remains stable for the duration of the study.
  • Neuroleptic medication free for at least three months (ASD+Hyper and ASD+Normal only).

Exclusion:

  • Same exclusion criteria as the Screening Visit.
  • Allergy to lanolin or soy (Hypo+ASD only).
  • Non-verbal mental age below 18 months as measured by the developmentally-appropriate form of the Stanford-Binet-V, Differential Abilities Scale, or the Mullen Scales of Early Learning (N.B. potential subjects who test below 18 months of age, but are otherwise eligible, may be admitted to the study following a case review convened by the Multisite Steering Committee).
  • Did not meet the criteria for an ASD during the Characterization Visit.

Double-Blind, Placebo-Controlled trial phase for ASD+Hypo Only:

Inclusion:

  • Met Characterization Visit inclusion criteria and completed Characterization Visit procedures.
  • Met criteria for hypocholesterolemia in ASD.

Exclusion:

-Same exclusion criteria as the Characterization Visit.

Open-Label Trial for ASD+Hypo only:

Inclusion:

- Subject continues to meet double-blind, placebo-controlled trial phase inclusion criteria.

Exclusion:

- Subject started a neuroleptic medication or medication that affects cholesterol synthesis or metabolism.

Family Members of ASD+Hypo only:

Inclusion:

- Biological parent(s) and full or half-sibling(s) of any age.

Exclusion:

- Those individuals not willing to provide a blood sample or a saliva sample for DNA.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00965068

Locations
United States, Maryland
Kennedy Krieger Institute
Baltimore, Maryland, United States, 21205
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210-1240
Sponsors and Collaborators
Investigators
Principal Investigator: Forbes D Porter, M.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
ClinicalTrials.gov Identifier: NCT00965068     History of Changes
Other Study ID Numbers: 090203, 09-CH-0203
Study First Received: August 24, 2009
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Autism
Autism Spectrum Disorder
Cholesterol
Smith-Lemli-Opitz Syndrome
ASD
Pervasive Developmental Disorder
PPD-NOS

Additional relevant MeSH terms:
Disease
Autistic Disorder
Asperger Syndrome
Pathologic Processes
Child Development Disorders, Pervasive
Mental Disorders Diagnosed in Childhood
Mental Disorders

ClinicalTrials.gov processed this record on September 29, 2014